Takeda's Relugolix Launches in Japan: Who Else Is Developing GnRH-Targeted Therapies?

Author: Garfield

On January 8, 2019, Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) approved relugolix for the improvement of symptoms associated with uterine fibroids, including menorrhagia, lower abdominal pain, low back pain, and anemia. This marked the first approval by the Japanese PMDA of a gonadotropin-releasing hormone (GnRH) receptor antagonist for the treatment of uterine fibroids. The editor has leveraged the PharmCube database to outline the global competitive landscape of GnRH-targeted therapies for reference.

1. Overview of Relugolix

Figure 1. Structural formula of Relugolix (Data source: PharmCube database)

On January 8, 2019, relugolix, developed by Takeda, received approval from the Pharmaceuticals and Medical Devices Agency (PMDA) for marketing in Japan under the brand name Relumina® (oral tablets, each containing 40 mg of relugolix). It is indicated for the improvement of the following symptoms associated with uterine fibroids: menorrhagia, lower abdominal pain, low back pain, and anemia. In addition to its use in treating uterine fibroids, the drug is undergoing Phase III clinical trials in multiple countries for indications including pain associated with endometriosis and prostate cancer.

Figure 2. Basic Information on Relugolix (Data source: YaoDu Database)

Relugolix underwent Phase I clinical trials in Japan in January 2008 for pain associated with uterine fibroids and endometriosis, and it took 11 years until its final approval for marketing by the PMDA on January 8, 2019. The drug was initially developed by Takeda. In June 2016, Myovant Sciences (a company formed by Roivant and Takeda) obtained exclusive global rights, excluding Japan and other Asian countries. In May 2018, ASKA Pharmaceutical received authorization from Takeda for the exclusive development and commercialization of Relugolix in Japan. Specific milestone events are shown in Figure 3.

Figure 3. Milestones in the Development of Relugolix (Data source: Compiled by PharmCube)

Relugolix tablets were submitted for clinical trial approval in China on April 11, 2018, approved for clinical trials on July 6, 2018, and a Phase II/III clinical trial of Relugolix for the treatment of advanced prostate cancer was initiated in China on December 10, 2018.

2. Introduction to the GnRH Target

All GnRH decapeptides in nature are highly conserved sequences, with consistent length, N-terminus (pGlu-His-Trp-Ser), and C-terminus (Pro-Gly-NH2). As a key factor in the hypothalamic-pituitary-ovarian axis, GnRH is closely related to gonadal function. The hypothalamus periodically sends pulsatile GnRH signals to the pituitary gland, and only pulsatile GnRH release can induce the synthesis and secretion of gonadotropins. Continuous administration of GnRH desensitizes the pituitary gland and inhibits LH release [1]. GnRH-targeted drugs are classified into GnRH agonists and GnRH antagonists based on their mechanisms of action, as detailed in Table 1.

Table 1. Summary of Mechanisms of Action and Characteristics of GnRH Agonists and GnRH Antagonists

Source: Compiled by Yaodu

3. Marketed and Investigational GnRH-Targeting Drugs for the Treatment of Uterine Fibroids

Table 2. Statistics of Marketed Drugs Targeting GnRH for the Treatment of Uterine Fibroids

Data Source: PharmD Database

Relugolix is an orally active, non-peptide GnRH antagonist. A randomized, double-blind, Phase III non-inferiority clinical trial comparing relugolix with leuprorelin was conducted in Japan. The primary efficacy endpoint was the proportion of patients with a total menstrual blood loss assessment score of less than 10 between weeks 6 and 12 after administration. The proportion of patients with significantly reduced bleeding was similar in the relugolix and leuprorelin groups (82.2% vs. 83.1%), demonstrating that relugolix was non-inferior to leuprorelin. Compared with placebo, relugolix significantly alleviated pain associated with uterine fibroids (proportion of patients with a maximum Numerical Rating Scale [NRS] score ≤1: 56.1% in the relugolix group vs. 3.1% in the placebo group).

The main adverse reactions of this drug include hot flashes, irregular uterine bleeding, menorrhagia, headache, and excessive sweating. Less than 1% of patients experience menopausal depression due to the estrogen-lowering effect. Compared with GnRH agonists, which are all injectables, Relugolix is an oral tablet, offering greater convenience for patients. As a GnRH antagonist, it does not cause a "flare-up" effect. It offers flexibility, can be used at any stage of the menstrual cycle, inhibits the release of pituitary gonadotropins, has a rapid onset and short duration of action, and allows for quick recovery of pituitary function after discontinuation, demonstrating significant advantages over GnRH agonists.

GnRH agonists can significantly reduce the volume of uterine fibroids and the uterus in the treatment of uterine fibroids. After treatment, patients' dysmenorrhea, non-menstrual lower abdominal pain, and pressure symptoms can be rapidly alleviated. At three months of treatment, the uterine volume is reduced by an average of about 50% compared to before, with an amenorrhea rate exceeding 95%, and over 90% of patients achieving castrate levels of serum estradiol [2]. GnRH agonists are relatively expensive, and more than 70% of patients experience symptoms related to hypoestrogenemia. Patients may prematurely develop menopausal symptoms such as hot flashes, sweating, irritability, insomnia, emotional instability, decreased libido, joint pain, and osteoporosis as adverse reactions.

Leuprorelin more gently downregulates the function of the hypothalamic-pituitary-ovarian axis, gradually reducing hormone levels. Compared with triptorelin, it has better tolerability and a lower incidence of menopausal symptoms [3].

Table 3. Statistics of Clinical Investigational Drugs Targeting GnRH for the Treatment of Uterine Fibroids

Data Source: PharmCube Database

Elagolix and Linzagolix are both oral non-peptide GnRH antagonists currently in Phase III clinical trials for the management of excessive bleeding caused by uterine fibroids, among other indications. On July 4, 2017, AbbVie announced the results of the Phase IIb clinical trial of Elagolix, which met its primary endpoint after six months of treatment, demonstrating a significant reduction in heavy menstrual bleeding. These findings indicate that Elagolix significantly alleviates severe menstrual bleeding symptoms in patients with uterine fibroids. Both drugs have adopted a development strategy prioritizing post-marketing expansion of indications to include uterine fibroids, following initial approval for the treatment of pain associated with endometriosis.

4. Marketed and Investigational GnRH-Targeting Drugs for the Treatment of Endometriosis

Table 4. Statistics of Marketed Drugs Targeting GnRH for the Treatment of Endometriosis

Data Source: PharmaGo Database

GnRH-targeted drugs can serve as second-line treatments for menstrual pain caused by endometriosis.

GnRH agonists can downregulate pituitary function, leading to temporary medical castration and a hypoestrogenic state. They may also bind to GnRH agonist receptors in peripheral tissues, thereby inhibiting the activity of both eutopic and ectopic endometrial cells. The primary adverse effects are perimenopausal symptoms caused by hypoestrogenemia.

On July 23, 2018, the FDA approved elagolix for the treatment of moderate to severe pain associated with endometriosis. Elagolix is the first orally active, non-peptide GnRH antagonist. Results from Phase III clinical trials (the Elaris EM-I and Elaris EM-II studies) demonstrated that the drug significantly alleviates three types of endometriosis-associated pain—daily menstrual pelvic pain, non-menstrual pelvic pain, and dyspareunia—and is well tolerated. The adverse reactions to elagolix are similar to those of peptide GnRH agonists and GnRH antagonists, including hot flashes, headache, and a lesser impact on bone mineral density; these adverse reactions are generally mild to moderate in severity.

Compared with GnRH agonists, elagolix has higher oral bioavailability, avoids injection-induced pain and allergic reactions, and improves patient compliance. Compared with medroxyprogesterone acetate, elagolix reduces the burden of breakthrough bleeding, allows immediate restoration of the menstrual cycle after discontinuation, and is suitable for women planning to become pregnant.

Table 5. Summary of Clinically Investigational Drugs Targeting GnRH for the Treatment of Endometriosis

Data Source: PharmCube Database

In November 2015, Kissei Pharmaceutical licensed to ObsEva the global development and commercialization rights for the drug, excluding Asia. The drug was supplied by Kissei Pharmaceutical, and both parties conducted parallel development. Results from the Phase IIb clinical trial (the EDELWEISS study) demonstrated that linzagolix significantly reduced pelvic pain in patients with endometriosis, thereby meeting the primary endpoint. In May 2019, ObsEva announced the initiation of a Phase III clinical trial (the EDELWEISS 2 study, NCT03986944) to evaluate linzagolix (75 mg/day or 200 mg/day for a 3-month treatment period) in combination with add-back therapy versus placebo for the treatment of moderate-to-severe endometriosis-associated pain. ObsEva planned to submit a New Drug Application (NDA) to the FDA for linzagolix in the treatment of endometriosis the following year.

SHR7280 is a Class 1 new drug developed by Hengrui Medicine. It is the first domestically developed oral non-peptide GnRH antagonist in China. The core compound’s authorized Chinese patent is CN104884457B, covering pyrazolopyrimidinone or pyrrolotriazinone derivatives. Clinical trial approval was granted on April 16, 2018, and Phase I clinical trials for endometriosis were initiated on August 30, 2018. Hengrui’s development of drugs targeting this mechanism closely follows international advancements.

5. Marketed and Investigational GnRH-Targeting Drugs for the Treatment of Prostate Cancer

Table 6. Statistics of Marketed Drugs Targeting GnRH for the Treatment of Prostate Cancer

Data Source: Pharmadex Database

Prostate cancer is an androgen-dependent malignant tumor. For patients who are not suitable for radical resection, the preferred treatment method is endocrine therapy, including GnRH agonists and GnRH antagonist drug treatments.

GnRH antagonists can directly and rapidly suppress the hypothalamic-pituitary-gonadal axis, thereby inhibiting tumor cell growth. Abarelix and degarelix are both peptide GnRH antagonists. Abarelix was the first GnRH antagonist approved by the U.S. FDA for the treatment of prostate cancer; however, it was withdrawn from the market one year after launch due to severe adverse reactions caused by systemic hypersensitivity responses triggered by histamine release. To enhance binding affinity to the GnRH receptor, improve bioavailability, increase stability against enzymatic degradation, and prolong half-life, Ferring Pharmaceuticals developed degarelix, which features a long-acting profile and minimal histamine release, and is approved for the treatment of hormone-sensitive advanced prostate cancer.

Table 7. Summary of Clinical Investigational Drugs Targeting GnRH for the Treatment of Prostate Cancer

Data Source: PharmCube Database

Currently, only Relugolix and Ozarelix are being developed for prostate cancer indications. Ozarelix, a fourth-generation peptide GnRH antagonist, is in Phase II clinical trials.

In addition to the indications for uterine fibroids, endometriosis, and prostate cancer, GnRH agonists are also used in assisted reproduction, abnormal uterine bleeding, precocious puberty, infertility, polycystic ovary syndrome (PCOS), premature ovarian failure, ovarian cancer, and breast cancer. GnRH antagonists are also used in assisted reproduction to prevent premature luteinizing hormone (LH) surges and control ovarian stimulation; representative marketed drugs include ganirelix and cetrorelix.

6. Global Market for Approved GnRH-Targeting Drugs

The global market size for marketed drugs targeting GnRH has shown a steady growth trend. In 2018, the total global sales of GnRH agonists and antagonists reached $4.4 billion. The top three drugs were the GnRH agonists leuprorelin, goserelin, and triptorelin, accounting for 56.6%, 17.2%, and 12.2% of the market share, respectively. The global sales of marketed peptide-based GnRH antagonists—cetrorelix, degarelix, and ganirelix—remained stable at $140–150 million. With the successive approvals and expanding indications of elagolix and relugolix, the landscape of the GnRH-targeted drug market is being reshaped, and oral non-peptide GnRH antagonists are poised to capture market share from GnRH agonists.

Figure 4. Global Sales of GnRH-Targeted Drugs in 2018 (Source: IMS Database)

7. PharmCube Perspectives

GnRH-targeted drugs include GnRH agonists, peptide GnRH antagonists, and oral non-peptide GnRH antagonists. Compared with GnRH agonists, GnRH antagonists do not cause a "flare-up" effect. They offer flexibility and can be administered at any stage of the menstrual cycle. They inhibit the release of pituitary gonadotropins, have a rapid onset and short duration of action, allow for rapid recovery of pituitary function after discontinuation, and exhibit dose-dependent inhibitory effects.

Oral non-peptide GnRH antagonists offer high oral bioavailability, eliminate injection-related pain and allergic reactions, provide convenient administration, improve patient compliance, and avoid the allergic reactions associated with peptide GnRH antagonists. Consequently, oral non-peptide GnRH antagonists represent a focal point and key development trend in the exploration of this therapeutic target.

Currently, GnRH-targeted drugs are primarily being developed for indications such as uterine fibroids, endometriosis, and prostate cancer. Other potential indications include assisted reproduction, abnormal uterine bleeding, precocious puberty, infertility, polycystic ovary syndrome (PCOS), premature ovarian failure, ovarian cancer, breast cancer, and the prevention of premature luteinizing hormone surges to control ovarian stimulation.

As the global market size for GnRH-targeted drugs is experiencing a steady but modest growth trend, and GnRH agonists such as leuprorelin, goserelin, and triptorelin are well-established among physicians—with long-acting formulations already developed—it is difficult to alter prescribing habits. Consequently, pharmaceutical companies have shown limited enthusiasm and are pursuing few clinical-stage candidates in this area.

With the successive approvals of elagolix and relugolix, non-peptide GnRH antagonists are poised to disrupt the existing market landscape by leveraging the advantages of oral tablet formulation, their unique mechanisms of action, and efficacy comparable to that of GnRH agonists, thereby gradually capturing market share from GnRH agonists. In addition to these two agents, linzagolix, developed by Kissei Pharmaceutical/ObsEva, planned to submit a New Drug Application to the FDA in 2020 for the treatment of endometriosis, which is expected to further expand the market share of oral non-peptide GnRH antagonists.

Hengrui’s SHR7280 is the first orally administered, non-peptide GnRH antagonist independently developed in China. Currently in Phase I clinical trials for the indication of endometriosis, it keeps pace with international advancements.

Overall, the market sales of GnRH-targeted drugs are still dominated by GnRH agonists, such as leuprolide, goserelin, and triptorelin, with leuprolide alone accounting for half of the total market share. With the successive launch of oral non-peptide GnRH antagonists, these agents are expected to capture market share from GnRH agonists and disrupt the existing market landscape.

Abbreviations

GnRH-ant, Gonadotropin-releasing hormone receptor antagonists, Gonadotropin-releasing hormone receptor antagonists

LH, Luteinizing Hormone, Luteinizing Hormone

FSH, Follicle-Stimulating Hormone, Follicle-Stimulating Hormone

References

1. Wang Rulong, Yao Yuanqing, Pharmaceutical Research on Gonadotropin-Releasing Hormone Antagonists, Chin. J. Clin. Pharmacol., 2019, 35:1221-1224.

2. Chinese expert consensus on the diagnosis and treatment of uterine fibroids, Chinese Journal of Obstetrics and Gynecology, 2017, 52:793-800.

3. Z.Li, H. Y. Zhu, et al, A randomized study comparing the side effects andhormonal status of triptorelin and leuprorelin following conservativelaparoscopic surgery for ovarian endometriosis in Chinese women., Eur. JObstet. Gynecol Reprod. Biol., 2014, 183:164-168.

4. Guidelines for the diagnosis and treatment of endometriosis, Chinese Journal of Obstetrics and Gynecology, 2015, 3:161-169.

5. FDA Official Website

Original Title: Takeda’s Relugolix Launches in Japan; Who Else Is Pursuing GnRH Target R&D?

*Disclaimer: This article was written by an author contributing to Sina Medical News. The views expressed are solely those of the author and do not represent the position of Sina Medical News.